CN104098621B - Beta-arbutin crystal III substance, preparation method, composition and application thereof - Google Patents
Beta-arbutin crystal III substance, preparation method, composition and application thereof Download PDFInfo
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Abstract
The invention discloses a beta-arbutin crystal III (chemical name: 4-hydroxyphenyl-beta-D-glucopyranoside monohydrate, english name: arbutin monohydrate), a preparation method, a composition and application thereof. Specifically, the invention discloses that beta-arbutin compound exists in a crystal III type solid substance state form under a solid state; a preparation method of a crystal III type solid substance sample; the beta-arbutin crystal III substance is used as an active ingredient in the preparation of antibacterial and anti-inflammatory drugs and cosmetics.
Description
Technical Field
The invention relates to a crystal III solid substance state form which discovers that beta-arbutin exists in a solid state; relates to a preparation method of a crystal III type sample; relates to a pharmaceutical composition or cosmetic containing beta-arbutin crystal III and mixed crystal forms containing the crystal III in any proportion; the invention also relates to application of the beta-arbutin crystal substance as an active ingredient of a medicine or a cosmetic in preparation of antibacterial and anti-inflammatory medicines and cosmetics.
Background
Beta-arbutin crystal III (chemical name: 4-hydroxyphenyl-beta-D-glucopyranoside monohydrate, english name: arbutin monohydrate) has the following molecular structural formula:
cosmetic compositions containing N-ethoxycarbonyl-4-amino-phenol and arbutin or derivatives thereof and/or ellagic acid or derivatives thereof according to the invention of III-Shewang Li Ye D-M-Fam are described in Chinese patent CN1302599A (publication No.) " [1] The preparation method of the arbutin cosmetic composition is disclosed.
In Chinese patent CN1481233A (publication No. "skin whitening composition comprising arbutin and glucosidase as active ingredients" invented by Gao Tai Limited " [2] Which relates to a skin whitening composition comprising arbutin.
A preparation method of a gel cosmetic for resolving spots and whitening disclosed in Luo Xiuying and Liang Yuzhen is described in Chinese patent CN1228300A (publication number) " [3] The preparation method of the gel cosmetic containing arbutin for eliminating freckle and whitening is disclosed.
Chinese patent CN1208608A (publication No.) describes the use of arbutin monoesters of M.Phillipe invention as depigmenting agents " [4] Among these are the use of arbutin monoesters as depigmenting or bleaching agents for human skin and the like in topically applied compositions.
Chinese patent CN1608693A (publication No.) describes "Ginseng radix and radix Panacis Quinquefolii containing arbutin" and its preparation method " [5] The preparation method of the arbutin-containing ginseng and American ginseng is provided.
In Chinese patent CN1633980A (publication No.)Formulated cosmetic " [6] Among them, it relates to a cosmetic made of ginseng containing arbutin.
In Chinese patent CN1635139A (publication No.), liu Chunqiao of the invention of "method for producing alpha-arbutin by fermentation" is described " [7] Which relates to a preparation method of alpha-arbutin.
A preparation method of alpha-arbutin invented by Chen Guorong, wang Chaoxia and Shi Xiaoxin is described in Chinese patent CN1724551A (publication No.) " [8] The preparation process of alpha-arbutin includes the final step of re-crystallizing solvent petroleum ether (60-90 deg.c): ethyl acetate=9 to 7:1.
in Chinese patent CN1727493A (publication No.), there is described "method for synthesizing alpha-arbutin by catalyzing free cells or immobilized cells" of Zhang Peng, zhang Shurong, liu Chunqiao, etc " [9] The preparation method of alpha-arbutin by catalyzing and synthesizing free cells or immobilized cells of Xanthomonas campestris CGMCC No.1243 is disclosed, and water is adopted as a recrystallization solvent in the last step.
In chinese patent CN101247816a (publication No.) a description is given of M-clinoinvention "molecular complexes comprising arbutin, ascorbic acid, oleuropein and its derivatives and their related uses in the medical field" [10] Wherein a molecular complex comprising fruit glycoside, ascorbic acid, oleuropein or its derivatives and related applications in the medical field are involved.
In Chinese patent CN101732169A (publication No.), wang Juan of the invention, an arbutin multifunctional skin care lotion is described " [11] The multifunctional skin care lotion containing arbutin is disclosed.
A method for producing A-arbutin by fermenting and transforming rhizopus is disclosed in Liang Jingjuan, pang Zongwen and Feng in Chinese patent CN101597631A (publication No.) " [12] Wherein relates to a method for producing A-arbutin by fermenting and transforming rhizopus.
"alpha-D-glucose pentaacetate" invented by Li Anliang, yang Shuqin, guo Xiuru is described in Chinese patent CN102040636A (publication No.)Synthesis of beta-arbutin " [13] The method for synthesizing beta-arbutin by using alpha-D-glucose pentaacetate as a raw material is characterized by comprising the step of synthesizing a key intermediate, wherein ethanol and water are adopted as a recrystallization solvent in the last step.
In Chinese patent CN102093442A (publication No.), zhao Yugong, wang Zhenyu and Wangjinling invention are described as a method for separating and purifying arbutin from blueberries " [14] The method for separating and purifying the arbutin extracted from blueberry pomace comprises the step of adopting water as a recrystallization solvent in the last step.
In Chinese patent CN102505031A (publication No.), ji Xiangjun, peng Feiyu, qian Weidong, shi Chunyang "method for synthesizing arbutin by converting hydroquinone from hairy root of Scutellariae radix" [15] Relates to a method for synthesizing arbutin by converting hydroquinone by using hairy roots of scutellaria baicalensis.
In Chinese patent CN102329838A (publication No.), du Gang, yang Haiying "a process for producing alpha-arbutin by microbial transformation" of the invention is described " [16] The method for producing alpha-arbutin by transformation of Aspergillus niger strains is related.
In Chinese patent CN102517361A (publication No.), there is described "method for synthesizing arbutin catalyzed by lipase" of the invention Deng Li, liu Chunqiao, wang Fang, tan Tianwei, nie Kaili, cao Xi " [17] The preparation method of arbutin by catalyzing and synthesizing with free or immobilized porcine pancreatic lipase is disclosed.
In Chinese patent CN102517362A (publication No.), wang Fang, liu Chunqiao, deng Li, tan Tianwei, nie Kaili, cao Xi "a method for synthesizing alpha-arbutin by lipase catalysis" is described " [18] The preparation process of alpha-arbutin catalyzed with free or immobilized candida lipase includes the final re-crystallization with water.
In Chinese patent CN102697672A (publication No.), xia Jiang and Chen Yanling "arbutin multiple emulsion" and its preparation method "are described" [19] Wherein an arbutin multiple emulsion is involved, the carrier is loaded with an arbutin active ingredientParts by weight.
The article "Arbutin: isolation, X-ray structure and computional studies" by Jacek E.Nycz et al is described in Japanese journal Journal of Molecular Structure " [20] Wherein, the beta-arbutin crystal form containing 0.5 water molecules is involved.
The invention discovers the state and the preparation method of the beta-arbutin crystal III solid substance containing 1 molecule of crystal water, which are different from the contents of the patent or literature research reports.
The invention aims to start from the research on the existence state of the crystal form solid substance of beta-arbutin, search and find the existence type and state characteristics of the crystal form solid substance on the raw material level of the active ingredients of medicines and cosmetics through the crystal form screening technology and the crystal form biological activity evaluation technology, combine the crystal form substance with the biological availability research, and provide basic scientific data for searching, finding and developing the dominant medicinal crystal form solid substance of beta-arbutin with the optimal clinical curative effect; meanwhile, scientific basis is provided for applying national or international intellectual property patent protection on the basis of the raw material substance of the beta-arbutin solid medicine.
Disclosure of Invention
One of the purposes of the present invention is: providing the existence state and description mode of beta-arbutin crystal III type solid substance.
The second object of the present invention is: provides a preparation method of a beta-arbutin crystal III type solid substance sample.
The third object of the present invention is: provides a solid medicine containing beta-arbutin crystal III pure product or mixed crystal form containing crystal III in any proportion and a composition thereof.
The fourth object of the present invention is: providing a pharmaceutical composition using beta-arbutin crystal III solid substance as a pharmaceutical active ingredient, wherein the daily dosage of the pharmaceutical composition is in the range of 10-500 mg; a cosmetic containing a beta-arbutin crystal form solid substance as an active ingredient, wherein the daily dose is 100-1000 mg.
The fifth object of the present invention is: providing a preparation method of tablets, capsules, pills, injection and sustained-release or controlled-release preparation medicaments for clinical use by using a crystal III solid substance of beta-arbutin as a raw material of a medicinal active ingredient; cosmetic is provided as a solid, suspension, emulsion or paste using a beta-arbutin crystalline solid substance as an active ingredient.
The sixth object of the present invention is: the beta-arbutin crystal III substance can improve the blood concentration of organisms due to the crystal substance in the process of treating diseases, thereby playing a role in effective treatment.
The seventh object of the present invention is: provides the application of using the beta-arbutin crystal III type solid substance as an active ingredient raw material in the preparation of antibacterial and anti-inflammatory drugs and cosmetics.
The invention provides a preparation method of a crystal III type solid substance form and a crystal III type sample of a beta-arbutin compound in a solid state; the application of the medicine and the composition thereof which are prepared and developed by using different crystal forms of beta-arbutin as active ingredients in preparing antibacterial and anti-inflammatory medicines and cosmetics is found.
Technical characteristics of
1. Morphology characterization of crystalline form III solid sample of β -arbutin:
the beta-arbutin crystal III solid substance is characterized by comprising a crystal water component, wherein the ratio of beta-arbutin molecules to crystal water molecules is 1:1, and the beta-arbutin crystal III solid substance shows orthorhombic symmetry and has a space group of P2 when analyzed by single crystal X-ray diffraction 1 2 1 2 1 The unit cell parameter value is
α=90.00°，β=90.00°，γ=90.00°，/>
Z=8. Fig. 1 shows a projection diagram of beta-arbutin crystal III type molecular three-dimensional structure, fig. 2 shows a unit cell stacking diagram of beta-arbutin crystal III type sample molecules along an a axis, and table 1 shows non-hydrogen atom coordinate parameters of beta-arbutin crystal III type.
TABLE 1 beta-arbutin Crystal III non-Hydrogen atom coordinate parameter and equivalent temperature factor value
1.2 the beta-arbutin crystal form III solid substance according to the invention is characterized in that when powder X-ray diffraction analysis is used, cuK is used α Under radiation experimental conditions, the diffraction peak positions are shown as follows: 2-Theta value (°) or d value #)
) And diffraction peak relative intensity: the peak Height value (Height%) or the peak Area value (Area%) is a solid material when the following characteristic peaks are present (table 2, fig. 3):
TABLE 2 powder X-ray diffraction peak of arbutin Crystal III solid sample
The solid substance of beta-arbutin crystal form III according to the invention is characterized by being in the form 3527, 3371, 3324, 3219, 3040, 2945, 2910, 2820, 2692, 2111, 1999, 1967, 1862, 1650, 1510, 1440, 1400, 1372, 1351, 1328, 1308, 1270, 1254, 1207, 1194, 1110, 1100, 1095, 1080, 1063, 1033, 997, 945, 908, 892, 858, 830, 776, 719cm when analyzed by infrared spectrum -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 (FIG. 4).
2. The preparation method of the beta-arbutin crystal III type sample is characterized in that:
the preparation method of the beta-arbutin crystal III type sample is characterized in that water, hydrous ethanol, ethanol or a mixed solvent consisting of the solvent and methanol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-propanol, isopropanol and n-butanol is used, the beta-arbutin crystal III type solid substance is obtained by completely dissolving the beta-arbutin sample at 15-60 ℃ and removing the solvent under the experimental conditions of the environment temperature of 4-80 ℃ and the relative humidity of 10-75% and the normal pressure or vacuum.
2.2 the preparation method of the beta-arbutin crystal III solid substance is characterized in that the beta-arbutin crystal III solid substance can be obtained by using an anhydrous beta-arbutin sample under the conditions that the relative humidity of the environment is 50% -100% and the standing time is longer than 10 hours.
3. Crystalline form component, administration dose and pharmaceutical preparation composition characteristics of beta-arbutin:
the beta-arbutin mixed crystal solid substance is characterized by containing beta-arbutin crystal III component in any proportion.
3.2 the pharmaceutical composition or cosmetic according to the present invention is characterized by comprising beta-arbutin crystalline form III or comprising beta-arbutin mixed crystalline solid substance and pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition of the invention, the daily dosage of the beta-arbutin is within the range of 10-500 mg.
3.4 the daily dosage of beta-arbutin of the cosmetic related to the invention is in the range of 100-1000 mg.
3.5 the pharmaceutical composition according to the invention is characterized in that the pharmaceutical composition is in the form of various tablets, capsules, pills, injections, sustained release preparations and controlled release preparations.
3.6 the cosmetic according to the present invention is characterized in that the cosmetic is in the form of a solid, suspension, emulsion or paste.
3.7 the invention relates to the application of beta-arbutin crystal III or beta-arbutin crystal III mixed crystal component containing any proportion in the preparation of antibacterial and anti-inflammatory drugs and cosmetics.
Drawings
FIG. 1 beta-arbutin crystal III type molecular stereo structure projection diagram
FIG. 2 unit cell stacking diagram of beta-arbutin crystal form III sample molecule along a-axis
FIG. 3 powder X-ray diffraction pattern of arbutin crystal form III solid sample
FIG. 4 is an infrared absorption spectrum of a sample of beta-arbutin crystal form III
Detailed Description
The following examples are given for better illustration of the technical solution of the present invention, but the present invention is not limited thereto.
Example 1
Preparation method of beta-arbutin crystal III sample 1:
200mg of the beta-arbutin bulk drug is dissolved in 20ml of ethanol/ethyl acetate (2:1), the sample is completely dissolved in water bath at 50 ℃ and kept stand for 15 days at 20 ℃ to obtain single crystals, and the crystals are colorless and transparent blocks. The obtained crystal sample was subjected to single crystal X-ray diffraction analysis, and the analysis showed orthorhombic symmetry, and the space group was P2 1 2 1 2 1 The unit cell parameter value is
α=90.00°，β=90.00°，γ=90.00°，/>
Z=8, indicating that the obtained sample is β -arbutin crystalline form III solid substance.
Preparation method of beta-arbutin crystal III sample 2:
200mg of the beta-arbutin bulk drug is heated and dissolved in 20ml of water at 50 ℃, the solution is filtered while the solution is hot to obtain a clear solution, the clear solution is subjected to rotary evaporation by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 60 ℃ and the rotating speed is 90rpm, the time is 20min, the sample is dried under reduced pressure to obtain 173mg of beta-arbutin solid substance, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 3:
200mg of beta-arbutin bulk drug is heated and dissolved in 25ml of ethanol at 45 ℃, filtered while the solution is hot to obtain a clear solution, rotary evaporation is carried out by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 45 ℃ and the rotating speed is 90rpm, the time is 15min, the sample is dried under reduced pressure to obtain 174mg of beta-arbutin solid substance, the obtained sample is subjected to powder X-ray diffraction analysis, and the diffraction pattern of the obtained sample is consistent with that of figure 3, so that the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 4:
100mg of beta-arbutin bulk drug is heated and dissolved in 30ml of acetone at 55 ℃, filtered while the solution is hot to obtain a clear solution, rotary evaporation is carried out by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 50 ℃ and the rotating speed is 90rpm, the time is 18min, 82mg of beta-arbutin solid substance is obtained by drying a sample under reduced pressure, and powder X-ray diffraction analysis is carried out on the obtained sample, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 5:
200mg of the beta-arbutin bulk drug is heated and dissolved in a mixed solvent system of 25ml of ethanol/water (1:1) at 55 ℃, filtered while the mixture is hot to obtain a clear solution, the clear solution is subjected to rotary evaporation by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 55 ℃ and the rotating speed is 90rpm, the time is 15min, the sample is subjected to reduced pressure drying to obtain 176mg of beta-arbutin solid substance, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, so that the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 6:
200mg of the beta-arbutin bulk drug is heated and dissolved in 25ml of isopropanol/water (1:1) mixed solvent system at 60 ℃, filtered while the mixture is hot to obtain clear solution, rotary evaporation is carried out by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 60 ℃ and the rotating speed is 90rpm, the time is 20min, the sample is dried under reduced pressure to obtain 171mg of beta-arbutin solid substance, and powder X-ray diffraction analysis is carried out on the obtained sample, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 7:
200mg of the beta-arbutin bulk drug is heated and dissolved in 30ml of acetonitrile/water (1:1) mixed solvent system at 50 ℃, filtered while the mixture is hot to obtain clear solution, rotary evaporation is carried out by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 60 ℃ and the rotating speed is 90rpm, the time is 15min, the sample is dried under reduced pressure to obtain 176mg of beta-arbutin solid substance, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 8:
200mg of the beta-arbutin bulk drug is heated and dissolved in 50ml of a methanol/chloroform (1:1) mixed solvent system at 60 ℃, filtered while the solution is hot to obtain a clear solution, rotary evaporation is carried out by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 55 ℃ and the rotating speed is 90rpm, the time is 20min, the sample is dried under reduced pressure to obtain 173mg of beta-arbutin solid matters, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid matters.
Preparation method of beta-arbutin crystal III sample 9:
200mg of the beta-arbutin bulk drug is heated and dissolved in 40ml of an acetone/water (1:1) mixed solvent system at 50 ℃, filtered while the mixture is hot to obtain a clear solution, the clear solution is subjected to rotary evaporation by a rotary evaporator, the pressure is 0.01Mpa, the water bath temperature is 50 ℃ and the rotating speed is 90rpm, the time is 20min, the sample is subjected to reduced pressure drying to obtain 170mg of beta-arbutin solid matters, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, so that the obtained sample is the beta-arbutin crystal III type solid matters.
Preparation method of beta-arbutin crystal III sample 10:
100mg of beta-arbutin bulk drug is heated and dissolved in 15ml of acetone/water (1:1) mixed solvent system at 50 ℃, filtered while the mixture is hot to obtain clear solution, and the clear solution is stood and crystallized under the conditions of 10 ℃ and 30% of ambient humidity and normal pressure to obtain 92mg of beta-arbutin solid sample, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of beta-arbutin crystal III sample 11:
100mg of beta-arbutin bulk drug is heated and dissolved in 18ml of dioxane/water (1:1) mixed solvent system at 60 ℃, filtered while the solution is hot to obtain clear solution, and the clear solution is stood and crystallized under the conditions of the ambient temperature of 25 ℃ and the ambient humidity of 15% and normal pressure to obtain 91mg of beta-arbutin solid sample, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of arbutin crystal III sample 12:
100mg of beta-arbutin bulk drug is heated and dissolved in a mixed solvent system of 20ml of ethanol/tetrahydrofuran (2:1) at 45 ℃, filtered while the mixture is hot to obtain a clear solution, and the clear solution is stood for crystallization under the conditions of 20 ℃ and 25% of ambient humidity and normal pressure to obtain 90mg of beta-arbutin solid sample, and the obtained sample is subjected to powder X-ray diffraction analysis, wherein the diffraction pattern is consistent with that of figure 3, and the obtained sample is beta-arbutin crystal III type solid substance.
Preparation method of arbutin crystal III sample 13:
100mg of anhydrous beta-arbutin bulk drug is placed under the condition of 95% of ambient humidity for 3 days to obtain 105mg of beta-arbutin solid sample, powder X-ray diffraction analysis is carried out on the obtained sample, and the diffraction pattern is consistent with that of figure 3, so that the obtained sample is beta-arbutin crystal III solid substance.
Example 2
Preparation method of combination pharmaceutical formulation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that beta-arbutin crystal III type pure product or mixed crystal solid substances containing any proportion of crystal III type are used as raw material medicines of the combined medicine, several excipients are used as auxiliary material components for preparing the combined medicine tablet, tablet samples with the drug content of 10-300 mg of each tablet are prepared according to a certain proportion, and the formula proportion of the tablet is shown in table 3:
preparation formula of table 3 beta-arbutin drug tablet
The method for preparing the beta-arbutin crystal III pure product or mixed crystal bulk drug containing any proportion of crystal III into the tablet preparation comprises the following steps: mixing several excipients and raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into soft material, sieving, granulating, oven drying, sieving, granulating, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Preparation method 2 (capsule) of the combined pharmaceutical preparation:
a preparation method of a combination drug capsule is characterized in that beta-arbutin crystal III pure product or mixed crystal solid matter containing any proportion of crystal III is used as a raw material drug of the combination drug, several excipients are used as auxiliary material components for preparing the combination drug capsule, a capsule sample with the drug content of 10-200 mg per tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in a table 4:
table 4 beta-arbutin crystal III type combined medicine capsule preparation raw material medicine and auxiliary material formula
The method for preparing the beta-arbutin crystal III pure product or mixed crystal bulk drug containing any proportion of crystal III into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into wet granule, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the beta-arbutin raw material medicine with several excipient auxiliary materials uniformly without using a granulating step, sieving, and directly encapsulating.
Cosmetic preparation method 3 (powder):
a preparation method of cosmetics is characterized in that beta-arbutin crystal III type pure products or mixed crystal solid substances containing any proportion of crystal III type are used as raw material medicines of cosmetics, several excipients are used as auxiliary material components for preparing cosmetics, powder with the content of 100-500 mg is prepared according to a certain proportion, and the formula proportion of the cosmetic powder is shown in a table 5:
table 5 beta-arbutin crystal III type cosmetic powder formulation
Pulverizing the above materials, sieving with 200 mesh sieve, mixing, tabletting, and packaging to obtain powder cake.
Cosmetic preparation method 4 (suspension):
a preparation method of cosmetics is characterized in that beta-arbutin crystal III type pure products or mixed crystal solid substances containing any proportion of crystal III type are used as raw material medicines of cosmetics, several excipients are used as auxiliary material components for preparing cosmetics, suspension with the content of 100-500 mg is prepared according to a certain proportion, and the formula proportion of the cosmetic suspension is shown in a table 6:
table 6 beta-arbutin crystal III type cosmetic suspension formulation
Pulverizing the above materials, sieving with 200 mesh sieve, adding glycerol and water, making into suspension by ultrasonic treatment, and bottling.
Cosmetic preparation method 5 (emulsion or paste):
a preparation method of cosmetics is characterized in that beta-arbutin crystal III type pure products or mixed crystal solid substances containing any proportion of crystal III type are used as raw material medicines of cosmetics, several excipients are used as auxiliary material components for preparing cosmetics, emulsion or paste with the content of 100-500 mg is prepared according to a certain proportion, and the formula proportion of the emulsion or paste is shown in a table 7:
table 7 beta-arbutin crystal III cosmetic emulsion or ointment formula
Pulverizing the above materials, sieving with 200 mesh sieve, adding appropriate amount of glycerol and water, stirring, mixing, and bottling.
Example 3
Dosage 1 (tablet) of β -arbutin crystalline combination drug:
the developed pharmaceutical composition is prepared by using a crystal form beta-arbutin sample as a pharmaceutical active ingredient, and is characterized in that the crystal form III beta-arbutin is used as the pharmaceutical active ingredient, the daily administration dosage is 30mg, and the pharmaceutical composition can be respectively prepared into a tablet type of 3 times per 1 tablet 10mg of ordinary tablet, 2 times per 1 tablet 15mg of ordinary tablet or 1 time per 1 tablet 30mg of ordinary tablet.
Dosage 2 (capsule) of β -arbutin crystalline combination drug:
the pharmaceutical composition is prepared and developed by using a crystal form beta-arbutin sample as a pharmaceutical active ingredient, and is characterized in that the crystal form III beta-arbutin is used as the pharmaceutical active ingredient, the daily administration dosage is 60mg, and the pharmaceutical composition can be prepared into capsules of 30mg for 2 times a day/1 granule/time and capsules of 60mg for 1 time a day/1 granule/time respectively.
Problems to be described: the beta-arbutin crystal form pharmaceutical composition has a plurality of factors on the administration dosage of the active ingredients, such as: the different uses for prevention and treatment cause different daily dosage; the different nature and severity of the illness cause the different daily dosage of the medicine; the sex, age and body surface area of patients are different, and the administration route, the administration times and the treatment purpose are different, so that the daily administration dosage is different; in addition, the absorption and blood concentration of the beta-arbutin crystal form sample are different, and the suitable dosage range of the beta-arbutin crystal form component is 0.01-300mg/kg body weight, preferably 10-100mg/kg body weight. When in use, different total dosage schemes of the crystal III type beta-arbutin active ingredients are formulated according to the actual requirements of prevention and treatment under different conditions, and the administration can be completed in a mode of multiple times or one time.
Dosage of beta-arbutin crystal form cosmetics:
the developed cosmetic night cream is prepared by using a crystal form beta-arbutin sample as an active ingredient, and is characterized in that the crystal form III beta-arbutin is used as the active ingredient of the cosmetic, the daily dosage is 200mg, and the cosmetic night cream is used at night.
The developed cosmetic foundation cream is prepared by using a crystal form beta-arbutin sample as an active ingredient, and is characterized in that the crystal form III beta-arbutin is used as the active ingredient of the cosmetic, and the daily dosage is 100mg and the cosmetic foundation cream is used in the morning.
Example 4
Stability advantage of beta-arbutin crystal form III:
the beta-arbutin crystal III solid substance belongs to a stable dominant crystal form, is stable in crystal form substance state under high temperature, high humidity and illumination conditions, is not easy to generate crystal transformation phenomenon, and has the advantage of stable crystal form substance state when being used for developing medicines and cosmetics.
Beta-arbutin crystal III absorption advantage:
the beta-arbutin crystal III solid substance belongs to an absorption dominant crystal form, and has higher absorption dominant characteristics than an anhydrous crystal form when being taken orally or externally used.
Reference to the literature
1. Chinese patent, publication No. CN1302599a
2. Chinese patent, publication No. CN1481233a
3. Chinese patent, publication No. CN1228300a
4. Chinese patent, publication No. CN1208608A
5. Chinese patent, publication No. CN1608693a
6. Chinese patent, publication No. CN1633980a
7. Chinese patent, publication No. CN1635139a
8. Chinese patent, publication No. CN1724551a
9. Chinese patent, publication No. CN1727493a
10. Chinese patent, publication No. CN101247816a
11. Chinese patent, publication No. CN101732169a
12. Chinese patent, publication No. CN101597631a
13. Chinese patent, publication No. CN102040636a
14. Chinese patent, publication No. CN102093442a
15. Chinese patent, publication No. CN102505031a
16. Chinese patent, publication No. CN102329838A
17. Chinese patent, publication No. CN102517361a
18. Chinese patent, publication No. CN102517362a
19. Chinese patent, publication No. CN102697672a
20.Jacek E.Nycz,Grzegorz Malecki,Monika Morag,et al.Arbutin:Isolation,X-ray structure and computional studies.Journal of Molecular Structure.2010,980:13-17.
Claims (11)
1. The beta-arbutin crystal III solid substance is characterized by containing a crystal water component, wherein the ratio of beta-arbutin molecules to crystal water molecules is 1:1, and the beta-arbutin crystal III solid substance shows orthorhombic symmetry when analyzed by single crystal X-ray diffraction, and the space group is P2 1 2 1 2 1 The unit cell parameter value is
α＝90.00°，β＝90.00°，γ＝90.00°，/>
Z=8; when powder X-ray diffraction analysis is used, cuK is used a Under radiation experimental conditions, the diffraction peak position is 2-Theta (°) or d +.>
The diffraction peak relative intensity peak Height value (Height%) or peak Area value (Area%) has the following expression:
when analyzed using infrared spectroscopy at 3527, 3371, 3324, 3219, 3040, 2945, 2910, 2820, 2692, 2111, 1999, 1967, 1862, 1650, 1510, 1440, 1400, 1372, 1351, 1328, 1308, 1270, 1254, 1207, 1194, 1110, 1100, 1095, 1080, 1063, 1033, 997, 945, 908, 892, 858, 830, 776, 719cm -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
2. The method for preparing the beta-arbutin crystal III solid substance according to claim 1, which is characterized in that water, hydrous ethanol, ethanol or a mixed solvent consisting of the solvent and methanol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-propanol, isopropanol and n-butanol is used, a beta-arbutin sample is completely dissolved at 15-60 ℃ and the solvent is removed under the experimental conditions of environment temperature of 4-80 ℃ and environment relative humidity of 10-75% and normal pressure or vacuum to obtain the beta-arbutin crystal III solid substance.
3. The method for preparing the beta-arbutin crystal III solid substance according to claim 1, which is characterized in that the beta-arbutin crystal III solid substance can be obtained by using an anhydrous beta-arbutin sample under the conditions that the relative humidity of the environment is 50% -100% and the standing time is longer than 10 hours.
4. A mixed crystal form solid substance of β -arbutin, characterized by containing the β -arbutin crystal form III ingredient of claim 1 in an arbitrary proportion.
5. A pharmaceutical or cosmetic composition comprising the β -arbutin crystalline form III pure product of claim 1 and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition or cosmetic comprising the β -arbutin mixed crystal solid substance of claim 4 and a pharmaceutically acceptable carrier.
7. Pharmaceutical composition according to claim 5 or 6, characterized in that the daily dosage of β -arbutin is in the range of 10-100 mg.
8. Cosmetic according to claim 5 or 6, characterized in that the daily dosage of β -arbutin is in the range of 100-1000 mg.
9. Pharmaceutical composition according to claim 5 or 6, characterized in that the composition is in the form of a tablet, capsule, pill, injection, slow release formulation or controlled release formulation.
10. Cosmetic product according to claim 5 or 6, characterized in that it is in the form of a solid, suspension, emulsion or paste.
11. Use of the beta-arbutin crystalline form III ingredient of claim 1 and/or the mixed crystalline form solid substance of claim 3 for the preparation of an antibacterial anti-inflammatory drug and a cosmetic.
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